1 5590 114 ROLE OF THE BICARBONATE-RESPONSIVE SOLUBLE ADENYLYL CYCLASE IN CHOLANGIOCYTE APOPTOSIS IN PRIMARY BILIARY CHOLANGITIS; A NEW HYPOTHESIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC FIBROSING CHOLANGIOPATHY CHARACTERIZED BY AN AUTOIMMUNE STEREOTYPE AND DEFECTIVE BILIARY BICARBONATE SECRETION DUE TO DOWN-REGULATION OF ANION EXCHANGER 2 (AE2). DESPITE THE AUTOIMMUNE FEATURES, IMMUNOSUPPRESSANTS ARE INEFFECTIVE WHILE TWO BILE ACID-BASED THERAPIES (URSODEOXYCHOLIC ACID AND OBETICHOLIC ACID) HAVE BEEN SHOWN TO IMPROVE BIOCHEMICAL AND HISTOLOGICAL FEATURES OF CHOLESTASIS AND LONG-TERM PROGNOSIS. HOWEVER, THE ETIOLOGY AND PATHOGENESIS OF PBC IS LARGELY UNKNOWN. RECENTLY, IT HAS BEEN SHOWN THAT MICRORNA-506 (MIR-506) ON CHROMOSOME X IS UP-REGULATED IN PBC CHOLANGIOCYTES AND SUPPRESSES AE2 EXPRESSION, WHICH SENSITIZES CHOLANGIOCYTES TO BILE SALT-INDUCED APOPTOSIS BY ACTIVATING SOLUBLE ADENYLYL CYCLASE (SAC), AN EVOLUTIONARILY CONSERVED BICARBONATE SENSOR. IN THIS REVIEW, WE DISCUSS THE EXPERIMENTAL EVIDENCE FOR THE EMERGING ROLE OF THE MIR-506-AE2-SAC AXIS IN PBC PATHOGENESIS. WE FURTHER HYPOTHESIZE THAT THE INITIAL DISEASE TRIGGER INDUCES AN X-LINKED EPIGENETIC CHANGE, LEADING TO A FEMALE-BIASED ACTIVATION OF THE MIR-506-AE2-SAC AXIS. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: CHOLANGIOCYTES IN HEALTH AND DISEASEEDITED BY JESUS BANALES, MARCO MARZIONI AND PETER JANSEN. 2018 2 5272 33 PROMOTER HYPERMETHYLATION OF THE AE2/SLC4A2 GENE IN PBC. BACKGROUND & AIMS: PATIENTS WITH PRIMARY BILIARY CHOLANGITIS (PBC) EXHIBIT REDUCED AE2/SLC4A2 GENE EXPRESSION IN THE LIVER AND PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS). AE2 ENCODES A CL(-)/HCO(3) (-) EXCHANGER INVOLVED IN BILIARY BICARBONATE SECRETION AND INTRACELLULAR PH REGULATION. REDUCED AE2 EXPRESSION IN PBC MAY BE PATHOGENIC, AS AE2-KNOCKOUT MICE REPRODUCE CHARACTERISTIC PBC FEATURES. HEREIN, WE AIMED TO IDENTIFY CPG-METHYLATION ABNORMALITIES IN AE2 PROMOTER REGIONS THAT MIGHT CONTRIBUTE TO THE REDUCED GENE TRANSCRIPTION IN PBC LIVERS AND PBMCS. METHODS: CPG-CYTOSINE METHYLATION RATES WERE INTERROGATED AT 1-BASE PAIR RESOLUTION IN UPSTREAM AND ALTERNATE AE2 PROMOTER REGIONS THROUGH PYROSEQUENCING OF BISULPHITE-MODIFIED GENOMIC DNA FROM LIVER SPECIMENS AND PBMCS. AE2A AND ALTERNATIVE AE2B1 AND AE2B2 MRNA LEVELS WERE MEASURED BY REAL-TIME PCR. HUMAN LYMPHOBLASTOID-T2 CELLS WERE TREATED WITH 5-AZA-2 -DEOXYCYTIDINE FOR DEMETHYLATION ASSAYS. RESULTS: AE2 PROMOTERS WERE FOUND TO BE HYPERMETHYLATED IN PBC LIVERS COMPARED TO NORMAL AND DISEASED LIVER SPECIMENS. RECEIVER OPERATING CHARACTERISTIC (ROC) CURVE ANALYSIS SHOWED THAT MINIMAL CPG-HYPERMETHYLATION CLUSTERS OF 3 AE2A-CPG SITES AND 4 ALTERNATE-AE2B2-CPG SITES SPECIFICALLY DIFFERENTIATED PBC FROM NORMAL AND DISEASED CONTROLS, WITH MEAN METHYLATION RATES INVERSELY CORRELATING WITH RESPECTIVE TRANSCRIPT LEVELS. ADDITIONALLY, IN PBMCS A MINIMAL CLUSTER OF 3 HYPERMETHYLATED AE2A-CPG SITES DISTINGUISHED PBC FROM CONTROLS, AND MEAN METHYLATION RATES CORRELATED NEGATIVELY WITH AE2A MRNA LEVELS IN THESE IMMUNE CELLS. ALTERNATE AE2B2/AE2B1 PROMOTERS IN PBMCS WERE CONSTITUTIVELY HYPERMETHYLATED, IN LINE WITH ABSENT ALTERNATIVE MRNA EXPRESSION IN DISEASED AND HEALTHY PBMCS. DEMETHYLATION ASSAYS TREATING LYMPHOBLASTOID-T2 CELLS WITH 5-AZA-2 -DEOXYCYTIDINE TRIGGERED AE2B2/AE2B1 EXPRESSION AND UPREGULATED AE2A-PROMOTER EXPRESSION. CONCLUSIONS: DISEASE-SPECIFIC HYPERMETHYLATION OF AE2 PROMOTER REGIONS AND SUBSEQUENT DOWNREGULATION OF AE2-GENE EXPRESSION IN THE LIVER AND PBMCS OF PATIENTS WITH PBC MIGHT BE CRITICALLY INVOLVED IN THE PATHOGENESIS OF THIS COMPLEX DISEASE. LAY SUMMARY: PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC IMMUNE-ASSOCIATED CHOLESTATIC LIVER DISEASE WITH UNCLEAR COMPLEX/MULTIFACTORIAL ETIOPATHOGENESIS AFFECTING MOSTLY MIDDLE-AGED WOMEN. PATIENTS WITH PBC EXHIBIT REDUCED EXPRESSION OF THE AE2/SLC4A2 GENE. HEREIN, WE FOUND THAT AE2 PROMOTER REGIONS ARE HYPERMETHYLATED IN THE LIVER AND PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH PBC. THIS INCREASED METHYLATION IS ASSOCIATED WITH DOWNREGULATED AE2-GENE EXPRESSION, WHICH MIGHT CONTRIBUTE TO THE PATHOGENESIS OF PBC. THEREFORE, NOVEL EPIGENETIC TARGETS MAY IMPROVE TREATMENT IN PATIENTS WITH PBC WHO RESPOND POORLY TO CURRENT PHARMACOLOGICAL THERAPIES. 2019 3 3327 30 HISTONE DEACETYLASE 4 PROMOTES CHOLESTATIC LIVER INJURY IN THE ABSENCE OF PROHIBITIN-1. PROHIBITIN-1 (PHB1) IS AN EVOLUTIONARILY CONSERVED PLEIOTROPIC PROTEIN THAT PARTICIPATES IN DIVERSE PROCESSES DEPENDING ON ITS SUBCELLULAR LOCALIZATION AND INTERACTOME. RECENT DATA HAVE INDICATED A DIVERSE ROLE FOR PHB1 IN THE PATHOGENESIS OF OBESITY, CANCER, AND INFLAMMATORY BOWEL DISEASE, AMONG OTHERS. DATA PRESENTED HERE SUGGEST THAT PHB1 IS ALSO LINKED TO CHOLESTATIC LIVER DISEASE. EXPRESSION OF PHB1 IS MARKEDLY REDUCED IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS AND BILIARY ATRESIA OR WITH ALAGILLE SYNDROME, TWO MAJOR PEDIATRIC CHOLESTATIC CONDITIONS. IN THE EXPERIMENTAL MODEL OF BILE DUCT LIGATION, SILENCING OF PHB1 INDUCED LIVER FIBROSIS, REDUCED ANIMAL SURVIVAL, AND INDUCED BILE DUCT PROLIFERATION. IMPORTANTLY, THE MODULATORY EFFECT OF PHB1 IS NOT DEPENDENT ON ITS KNOWN MITOCHONDRIAL FUNCTION. ALSO, PHB1 INTERACTS WITH HISTONE DEACETYLASE 4 (HDAC4) IN THE PRESENCE OF BILE ACIDS. HENCE, PHB1 DEPLETION LEADS TO INCREASED NUCLEAR HDAC4 CONTENT AND ITS ASSOCIATED EPIGENETIC CHANGES. REMARKABLY, HDAC4 SILENCING AND THE ADMINISTRATION OF THE HDAC INHIBITOR PARTHENOLIDE DURING OBSTRUCTIVE CHOLESTASIS IN VIVO PROMOTE GENOMIC REPROGRAMMING, LEADING TO REGRESSION OF THE FIBROTIC PHENOTYPE IN LIVER-SPECIFIC PHB1 KNOCKOUT MICE. CONCLUSION: PHB1 IS AN IMPORTANT MEDIATOR OF CHOLESTATIC LIVER INJURY THAT REGULATES THE ACTIVITY OF HDAC4, WHICH CONTROLS SPECIFIC EPIGENETIC MARKERS; THESE RESULTS IDENTIFY POTENTIAL NOVEL STRATEGIES TO TREAT LIVER INJURY AND FIBROSIS, PARTICULARLY AS A CONSEQUENCE OF CHRONIC CHOLESTASIS. 2015 4 5153 21 PPP2R2B HYPERMETHYLATION CAUSES ACQUIRED APOPTOSIS DEFICIENCY IN SYSTEMIC AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION CAUSES TARGET ORGAN DAMAGE IN PATIENTS WITH SYSTEMIC AUTOIMMUNE DISEASES. THE FACTORS THAT ALLOW THIS PROTRACTED RESPONSE ARE POORLY UNDERSTOOD. WE ANALYZED THE TRANSCRIPTIONAL REGULATION OF PPP2R2B (B55SS), A MOLECULE NECESSARY FOR THE TERMINATION OF THE IMMUNE RESPONSE, IN PATIENTS WITH AUTOIMMUNE DISEASES. ALTERED EXPRESSION OF B55SS CONDITIONED RESISTANCE TO CYTOKINE WITHDRAWAL-INDUCED DEATH (CWID) IN PATIENTS WITH AUTOIMMUNE DISEASES. THE IMPAIRED UPREGULATION OF B55SS WAS CAUSED BY INFLAMMATION-DRIVEN HYPERMETHYLATION OF SPECIFIC CYTOSINES LOCATED WITHIN A REGULATORY ELEMENT OF PPP2R2B PREVENTING CTCF BINDING. THIS PHENOTYPE COULD BE INDUCED IN HEALTHY T CELLS BY EXPOSURE TO TNF-ALPHA. OUR RESULTS REVEAL A GENE WHOSE EXPRESSION IS AFFECTED BY AN ACQUIRED DEFECT, THROUGH AN EPIGENETIC MECHANISM, IN THE SETTING OF SYSTEMIC AUTOIMMUNITY. BECAUSE FAILURE TO REMOVE ACTIVATED T CELLS THROUGH CWID COULD CONTRIBUTE TO AUTOIMMUNE PATHOLOGY, THIS MECHANISM ILLUSTRATES A VICIOUS CYCLE THROUGH WHICH AUTOIMMUNE INFLAMMATION CONTRIBUTES TO ITS OWN PERPETUATION. 2019 5 6584 21 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 6 5220 29 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION. 2018 7 3933 24 LIVER SINUSOIDAL ENDOTHELIAL CELLS ARE IMPLICATED IN MULTIPLE FIBROTIC MECHANISMS. CHRONIC LIVER DISEASES ARE ATTRIBUTED TO LIVER INJURY. DEVELOPMENT OF FIBROSIS FROM CHRONIC LIVER DISEASES IS A DYNAMIC PROCESS THAT INVOLVES MULTIPLE MOLECULAR AND CELLULAR PROCESSES. AS THE FIRST TO BE IMPACTED BY INJURY, LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSECS) ARE INVOLVED IN THE PATHOGENESIS OF LIVER DISEASES CAUSED BY A VARIETY OF ETIOLOGIES. MOREOVER, CAPILLARIZATION OF LSECS HAS BEEN RECOGNIZED AS AN IMPORTANT EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASES AND FIBROSIS. STUDIES HAVE REPORTED THAT VARIOUS CYTOKINES (SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR, TRANSFORMING GROWTH FACTOR-BETA), AND PATHWAYS (SUCH AS HEDGEHOG, AND NOTCH), AS WELL AS EPIGENETIC AND METABOLIC FACTORS ARE INVOLVED IN THE DEVELOPMENT OF LSEC-MEDIATED LIVER FIBROSIS. THIS REVIEW DESCRIBES THE COMPLEXITY AND PLASTICITY OF LSECS IN FIBROTIC LIVER DISEASES FROM SEVERAL PERSPECTIVES, INCLUDING THE CROSS-TALK BETWEEN LSECS AND OTHER INTRA-HEPATIC CELLS. MOREOVER, IT SUMMARIZES THE MECHANISMS OF SEVERAL KINDS OF LSECS-TARGETING ANTI-FIBROSIS CHEMICALS, AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDIES. 2021 8 4012 28 LOW-DENSITY GRANULOCYTES IN SYSTEMIC AUTOIMMUNITY AND AUTOINFLAMMATION. A BODY OF EVIDENCE HAS RE-ENERGIZED THE INTEREST ON THE ROLE NEUTROPHILS IN INFLAMMATORY AND AUTOIMMUNE CONDITIONS. FOR DECADES, NEUTROPHILS HAVE BEEN CONSIDERED A HOMOGENOUS POPULATION. NEVERTHELESS, ACCUMULATING EVIDENCE SUGGESTS THAT NEUTROPHILS ARE MORE VERSATILE AND HETEROGENEOUS THAN INITIALLY CONSIDERED. THE NOTION OF NEUTROPHIL HETEROGENEITY HAS BEEN SUPPORTED BY THE IDENTIFICATION OF LOW-DENSITY GRANULOCYTES (LDGS) IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER SYSTEMIC AUTOIMMUNE AND AUTOINFLAMMATORY CONDITIONS. TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND FUNCTIONAL ANALYSES SUPPORT THAT LDGS ARE A DISTINCT SUBSET OF PROINFLAMMATORY NEUTROPHILS IMPLICATED IN THE PATHOGENESIS OF SLE AND OTHER AUTOIMMUNE DISEASES. IMPORTANTLY, IT REMAINS INCOMPLETELY CHARACTERIZED WHETHER LDGS DETECTED IN OTHER INFLAMMATORY/AUTOIMMUNE CONDITIONS DISPLAY THE SAME PHENOTYPE THAT THOSE PRESENT IN SLE. A SHARED FEATURE OF LDGS ACROSS DISEASES IS THEIR ASSOCIATION WITH VASCULAR DAMAGE, AN IMPORTANT CONTRIBUTOR TO MORBIDITY AND MORTALITY IN CHRONIC INFLAMMATORY CONDITIONS. ADDITIONALLY, THE LACK OF SPECIFIC MARKERS TO IDENTIFY LDGS IN CIRCULATION OR IN TISSUE, MAKES IT A CHALLENGE TO ELUCIDATE THEIR ROLE IN THE PATHOGENESIS OF INFLAMMATORY AND AUTOIMMUNE CONDITIONS. IN THIS REVIEW, WE AIM TO EXAMINE THE EVIDENCE ON THE BIOLOGY AND THE PUTATIVE PATHOGENIC ROLE OF LDGS IN SYSTEMIC AUTOIMMUNE DISEASES. 2023 9 6421 27 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES. 2018 10 4968 26 PATHOLOGICAL MECHANISMS AND THERAPEUTIC OUTLOOKS FOR ARTHROFIBROSIS. ARTHROFIBROSIS IS A FIBROTIC JOINT DISORDER THAT BEGINS WITH AN INFLAMMATORY REACTION TO INSULTS SUCH AS INJURY, SURGERY AND INFECTION. EXCESSIVE EXTRACELLULAR MATRIX AND ADHESIONS CONTRACT POUCHES, BURSAE AND TENDONS, CAUSE PAIN AND PREVENT A NORMAL RANGE OF JOINT MOTION, WITH DEVASTATING CONSEQUENCES FOR PATIENT QUALITY OF LIFE. ARTHROFIBROSIS AFFECTS PEOPLE OF ALL AGES, WITH PUBLISHED RATES VARYING. THE RISK FACTORS AND BEST MANAGEMENT STRATEGIES ARE LARGELY UNKNOWN DUE TO A POOR UNDERSTANDING OF THE PATHOLOGY AND LACK OF DIAGNOSTIC BIOMARKERS. HOWEVER, CURRENT RESEARCH INTO THE PATHOGENESIS OF FIBROSIS IN ORGANS NOW INFORMS THE UNDERSTANDING OF ARTHROFIBROSIS. THE PROCESS BEGINS WHEN STRESS SIGNALS STIMULATE IMMUNE CELLS. THE RESULTING CASCADE OF CYTOKINES AND MEDIATORS DRIVES FIBROBLASTS TO DIFFERENTIATE INTO MYOFIBROBLASTS, WHICH SECRETE FIBRILLAR COLLAGENS AND TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA). POSITIVE FEEDBACK NETWORKS THEN DYSREGULATE PROCESSES THAT NORMALLY TERMINATE HEALING PROCESSES. WE PROPOSE TWO SUBTYPES OF ARTHROFIBROSIS OCCUR: ACTIVE ARTHROFIBROSIS AND RESIDUAL ARTHROFIBROSIS. IN THE LATTER THE FIBROGENIC PROCESSES HAVE RESOLVED BUT THE JOINT REMAINS STIFF. THE BEST THERAPEUTIC APPROACH FOR EACH SUBTYPE MAY DIFFER SIGNIFICANTLY. TREATMENT TYPICALLY INVOLVES SURGERY, HOWEVER, A PHARMACOLOGICAL APPROACH TO CORRECT DYSREGULATED CELL SIGNALLING COULD BE MORE EFFECTIVE. RECENT RESEARCH SHOWS THAT MYOFIBROBLASTS ARE CAPABLE OF REVERSING DIFFERENTIATION, AND UNDERSTANDING THE MECHANISMS OF PATHOGENESIS AND RESOLUTION WILL BE ESSENTIAL FOR THE DEVELOPMENT OF CELL-BASED TREATMENTS. THERAPIES WITH SIGNIFICANT PROMISE ARE CURRENTLY AVAILABLE, WITH MORE IN DEVELOPMENT, INCLUDING THOSE THAT INHIBIT TGF-BETA SIGNALLING AND EPIGENETIC MODIFICATIONS. THIS REVIEW FOCUSES ON PATHOGENESIS OF STERILE ARTHROFIBROSIS AND THERAPEUTIC TREATMENTS. 2019 11 5433 18 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION. 2002 12 3762 23 INTEGRATING THE TUMOR-SUPPRESSIVE ACTIVITY OF MASPIN WITH P53 IN RETUNING THE EPITHELIAL HOMEOSTASIS: A WORKING HYPOTHESIS AND APPLICABLE PROSPECTS. EPITHELIAL MALIGNANT TRANSFORMATION AND TUMOROUS DEVELOPMENT WERE BELIEVED TO BE CLOSELY ASSOCIATED WITH THE LOSS OF ITS MICROENVIRONMENT INTEGRITY AND HOMEOSTASIS. THE TUMOR-SUPPRESSIVE MOLECULES MASPIN AND P53 WERE DEMONSTRATED TO PLAY A CRUCIAL ROLE IN BODY EPITHELIAL AND IMMUNE HOMEOSTASIS. DOWNREGULATION OF MASPIN AND MUTATION OF P53 WERE FREQUENTLY ASSOCIATED WITH MALIGNANT TRANSFORMATION AND POOR PROGNOSIS IN VARIOUS HUMAN CANCERS. IN THIS REVIEW, WE FOCUSED ON SUMMARIZING THE PROGRESS OF THE MOLECULAR NETWORK OF MASPIN IN STUDYING EPITHELIAL TUMOROUS DEVELOPMENT AND ITS RESPONSE TO CLINIC TREATMENT AND TRY TO CLARIFY THE UNDERLYING ANTITUMOR MECHANISM. NOTABLY, MASPIN EXPRESSION WAS REPORTED TO BE TRANSCRIPTIONALLY ACTIVATED BY P53, AND THE TRANSCRIPTIONAL ACTIVITY OF P53 WAS DEMONSTRATED TO BE ENHANCED BY ITS ACETYLATION THROUGH INHIBITION OF HDAC1. AS AN ENDOGENOUS INHIBITOR OF HDAC1, MASPIN POSSIBLY POTENTIATES THE TRANSCRIPTIONAL ACTIVITY OF P53 BY ACETYLATING THE P53 PROTEIN. HEREBY, IT COULD FORM A "SELF-PROPELLING" ANTITUMOR MECHANISM. THUS, WE SUMMARIZED THAT, UPON STIMULATION OF CELLULAR STRESS AND BY INTEGRATING WITH P53, THE AROUSED MASPIN PLAYED THE EPIGENETIC SURVEILLANT ROLE TO PREVENT THE EPITHELIAL DIGRESSIONAL PROCESS AND RETUNE THE EPITHELIAL HOMEOSTASIS, WHICH IS INVOLVED IN ACTIVATING HOST IMMUNE SURVEILLANCE, REGULATING THE INFLAMMATORY FACTORS, AND FINE-TUNING ITS ASSOCIATED CELL SIGNALING PATHWAYS. CONSEQUENTIALLY, IN A NORMAL PHYSIOLOGICAL CONDITION, ACTIVATION OF THE ABOVE "SELF-PROPELLING" ANTITUMOR MECHANISM OF MASPIN AND P53 COULD REDUCE CELLULAR STRESS (E.G., CHRONIC INFECTION/INFLAMMATION, OXIDATIVE STRESS, TRANSFORMATION) EFFECTIVELY AND ACHIEVE CANCER PREVENTION. MEANWHILE, DESIGNING A STRATEGY OF MIMICKING MASPIN'S EPIGENETIC REGULATION ACTIVITY WITH INTEGRATING P53 TUMOR-SUPPRESSIVE ACTIVITY COULD ENHANCE THE CHEMOTHERAPY EFFICACY THEORETICALLY IN A PATHOLOGICAL CONDITION OF CANCER. 2022 13 4175 26 MELATONIN PROTECTS CHOLANGIOCYTES FROM OXIDATIVE STRESS-INDUCED PROAPOPTOTIC AND PROINFLAMMATORY STIMULI VIA MIR-132 AND MIR-34. BIOSYNTHESIS OF MELATONIN BY CHOLANGIOCYTES IS ESSENTIAL FOR MAINTAINING THE FUNCTION OF BILIARY EPITHELIUM. HOWEVER, THIS CYTOPROTECTIVE MECHANISM APPEARS TO BE IMPAIRED IN PRIMARY BILIARY CHOLANGITIS (PBC). MIR-132 HAS EMERGED AS A MEDIATOR OF INFLAMMATION IN CHRONIC LIVER DISEASES. THE EFFECT OF MELATONIN ON OXIDATIVE STRESS AND BILE ACID-INDUCED APOPTOSIS WAS ALSO EXAMINED IN CHOLANGIOCYES OVEREXPRESSING MIR506, AS A PBC-LIKE CELLULAR MODEL. IN PBC PATIENTS THE SERUM LEVELS OF MELATONIN WERE FOUND INCREASED IN COMPARISON TO HEALTHY CONTROLS. WHEREAS, IN CHOLANGIOCYTES WITHIN CIRRHOTIC PBC LIVERS THE MELATONIN BIOSYNTHETIC PATHWAY WAS SUBSTANTIALLY SUPPRESSED EVEN THOUGH THE EXPRESSIONS OF MELATONIN RATE-LIMITING ENZYME ARALKYLAMINE N-ACETYLTRANSFERASE (AANAT), AND CK-19 (MARKER OF CHOLANGIOCYTES) WERE ENHANCED. IN CHOLANGIOCYTES EXPOSED TO MITOCHONDRIAL OXIDATIVE STRESS MELATONIN DECREASED THE EXPRESSION OF PROAPOPTOTIC STIMULI (PTEN, BAX, MIR-34), WHICH WAS ACCOMPANIED BY THE INHIBITION OF A PIVOTAL MEDIATOR OF INFLAMMATORY RESPONSE NF-KAPPAB-P65 AND THE ACTIVATION OF ANTIAPOPTOTIC SIGNALING (MIR-132, BCL2). SIMILARLY, MELATONIN REDUCED BILE ACID-INDUCED PROAPOPTOTIC CASPASE 3 AND BIM LEVELS. IN SUMMARY, THE INSUFFICIENT HEPATIC EXPRESSION OF MELATONIN IN PBC PATIENTS MAY PREDISPOSE CHOLANGIOCYTES TO OXIDATIVE STRESS-RELATED DAMAGE. MELATONIN, VIA EPIGENETIC MODULATION, WAS ABLE TO SUPPRESS NF-KAPPAB SIGNALING ACTIVATION AND PROTECT AGAINST BILIARY CELLS APOPTOTIC SIGNALING. 2020 14 4002 19 LOSS OF P120 CATENIN AND LINKS TO MITOTIC ALTERATIONS, INFLAMMATION, AND SKIN CANCER. TUMOR FORMATION INVOLVES EPIGENETIC MODIFICATIONS AND MICROENVIRONMENTAL CHANGES AS WELL AS CUMULATIVE GENETIC ALTERATIONS ENCOMPASSING SOMATIC MUTATIONS, LOSS OF HETEROZYGOSITY, AND ANEUPLOIDY. HERE, WE SHOW THAT CONDITIONAL TARGETING OF P120 CATENIN IN MICE LEADS TO PROGRESSIVE DEVELOPMENT OF SKIN NEOPLASIAS ASSOCIATED WITH INTRINSIC NF-KAPPAB ACTIVATION. WE FIND THAT, SIMILARLY, SQUAMOUS CELL CARCINOMAS IN HUMANS DISPLAY ALTERED P120 AND ACTIVATED NF-KAPPAB. WE SHOW THAT EPIDERMAL HYPERPROLIFERATION ARISING FROM P120 LOSS CAN BE ABROGATED BY IKAPPAB KINASE 2 INHIBITORS. ALTHOUGH THIS UNDERSCORES THE IMPORTANCE OF THIS PATHWAY, THE ROLE OF NF-KAPPAB IN HYPERPROLIFERATION APPEARS ROOTED IN ITS IMPACT ON EPIDERMAL MICROENVIRONMENT BECAUSE AS P120-NULL KERATINOCYTES DISPLAY A GROWTH-ARRESTED PHENOTYPE IN CULTURE. WE TRACE THIS TO A MITOTIC DEFECT, RESULTING IN UNSTABLE, BINUCLEATED CELLS IN VITRO AND IN VIVO. WE SHOW THAT THE ABNORMAL MITOSES CAN BE AMELIORATED BY INHIBITING RHOA, THE ACTIVITY OF WHICH IS ABNORMALLY HIGH. CONVERSELY, WE CAN ELICIT SUCH MITOTIC DEFECTS IN CONTROL KERATINOCYTES BY ELEVATING RHOA ACTIVITY. THE ABILITY OF P120 DEFICIENCY TO ELICIT MITOTIC ALTERATIONS AND CHRONIC INFLAMMATORY RESPONSES, THAT TOGETHER MAY FACILITATE THE DEVELOPMENT OF GENETIC INSTABILITY IN VIVO, PROVIDES INSIGHTS INTO WHY IT FIGURES SO PROMINENTLY IN SKIN CANCER PROGRESSION. 2008 15 4665 20 NEW INSIGHTS AND ADVANCES IN PATHOGENESIS AND TREATMENT OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE. VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEO-IBD) IS CHARACTERIZED BY MULTIFACTORIAL CHRONIC RECURRENT INTESTINAL INFLAMMATION. COMPARED WITH ELDERLY PATIENTS, THOSE WITH VEO-IBD HAVE A MORE SERIOUS CONDITION, NOT RESPONSIVE TO CONVENTIONAL TREATMENTS, WITH A POOR PROGNOSIS. RECENT STUDIES FOUND THAT GENETIC AND IMMUNOLOGIC ABNORMALITIES ARE CLOSELY RELATED TO VEO-IBD. INTESTINAL IMMUNE HOMEOSTASIS MONOGENIC DEFECTS (IIHMDS) ARE CHANGED THROUGH VARIOUS MECHANISMS. RECENT STUDIES HAVE ALSO REVEALED THAT ABNORMALITIES IN GENES AND IMMUNE MOLECULAR MECHANISMS ARE CLOSELY RELATED TO VEO-IBD. IIHMDS CHANGE THROUGH VARIOUS MECHANISMS. EPIGENETIC FACTORS CAN MEDIATE THE INTERACTION BETWEEN THE ENVIRONMENT AND GENOME, AND GENETIC FACTORS AND IMMUNE MOLECULES MAY BE INVOLVED IN THE PATHOGENESIS OF THE ENVIRONMENT AND GUT MICROBIOTA. THESE DISCOVERIES WILL PROVIDE NEW DIRECTIONS AND IDEAS FOR THE TREATMENT OF VEO-IBD. 2022 16 3243 28 HEPATIC STEATOSIS IN HEPATITIS C IS A STORAGE DISEASE DUE TO HCV INTERACTION WITH MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN (MTP). LIVER STEATOSIS IS A FREQUENT HISTOLOGICAL FEATURE IN PATIENTS CHRONICALLY INFECTED WITH HEPATITIS C VIRUS (HCV). THE RELATIONSHIP BETWEEN HCV AND HEPATIC STEATOSIS SEEMS TO BE THE RESULT OF BOTH EPIGENETIC AND GENETIC FACTORS. IN VIVO AND IN VITRO STUDIES HAVE SHOWN THAT HCV CAN ALTER INTRAHEPATIC LIPID METABOLISM BY AFFECTING LIPID SYNTHESIS, OXIDATIVE STRESS, LIPID PEROXIDATION, INSULIN RESISTANCE AND THE ASSEMBLY AND SECRETION OF VLDL. MANY STUDIES SUGGEST THAT HCV-RELATED STEATOSIS MIGHT BE THE RESULT OF A DIRECT INTERACTION BETWEEN THE VIRUS AND MTP. IT HAS BEEN DEMONSTRATED THAT MTP IS CRITICAL FOR THE SECRETION OF HCV PARTICLES AND THAT INHIBITION OF ITS LIPID TRANSFER ACTIVITY REDUCES HCV PRODUCTION. HOWEVER, HIGHER DEGREES OF HEPATIC STEATOSIS WERE FOUND IN CHRONIC HEPATITIS C PATIENTS CARRYING THE T ALLELE OF MTP -493G/T POLYMORPHISM THAT SEEMS TO BE ASSOCIATED WITH INCREASED MTP TRANSCRIPTION. WE PROPOSE HERE THAT LIVER STEATOSIS IN HEPATITIS C COULD BE A STORAGE DISEASE INDUCED BY THE EFFECTS OF THE VIRUS AND OF ITS PROTEINS ON THE INTRACELLULAR LIPID MACHINERY AND ON MTP. AVAILABLE DATA SUPPORT THE HYPOTHESIS THAT HCV MAY MODULATE MTP EXPRESSION AND ACTIVITY THROUGH A NUMBER OF MECHANISMS SUCH AS INHIBITION OF ITS ACTIVITY AND TRANSCRIPTIONAL CONTROL. INITIAL UP REGULATION COULD FAVOUR PROPAGATION OF HCV WHILE DOWN REGULATION IN CHRONIC PHASE COULD CAUSE IMPAIRMENT OF TRIGLYCERIDE SECRETION AND EXCESSIVE LIPID ACCUMULATION, WITH ABNORMAL LIPID DROPLETS FACILITATING THE "STORAGE" OF VIRUS PARTICLES FOR PERSISTENT INFECTION. 2010 17 222 20 ACUTE LIVER STEATOSIS TRANSLATIONALLY CONTROLS THE EPIGENETIC REGULATOR MIER1 TO PROMOTE LIVER REGENERATION IN A STUDY WITH MALE MICE. THE EARLY PHASE LIPID ACCUMULATION IS ESSENTIAL FOR LIVER REGENERATION. HOWEVER, WHETHER THIS ACUTE LIPID ACCUMULATION CAN SERVE AS SIGNALS TO DIRECT LIVER REGENERATION RATHER THAN SIMPLY PROVIDING BUILDING BLOCKS FOR CELL PROLIFERATION REMAINS UNCLEAR. THROUGH IN VIVO CRISPR SCREENING, WE IDENTIFY MIER1 (MESODERM INDUCTION EARLY RESPONSE 1) AS A KEY EPIGENETIC REGULATOR THAT BRIDGES THE ACUTE LIPID ACCUMULATION AND CELL CYCLE GENE EXPRESSION DURING LIVER REGENERATION IN MALE ANIMALS. PHYSIOLOGICALLY, LIVER ACUTE LIPID ACCUMULATION INDUCES THE PHOSPHORYLATION OF EIF2S1(EUKARYOTIC TRANSLATION INITIATION FACTOR 2), WHICH CONSEQUENTLY ATTENUATED MIER1 TRANSLATION. MIER1 DOWNREGULATION IN TURN PROMOTES CELL CYCLE GENE EXPRESSION AND REGENERATION THROUGH CHROMATIN REMODELING. IMPORTANTLY, THE LIPIDS-EIF2S1-MIER1 PATHWAY IS IMPAIRED IN ANIMALS WITH CHRONIC LIVER STEATOSIS; WHEREAS MIER1 DEPLETION SIGNIFICANTLY IMPROVES REGENERATION IN THESE ANIMALS. TAKEN TOGETHER, OUR STUDIES IDENTIFY AN EPIGENETIC MECHANISM BY WHICH THE EARLY PHASE LIPID REDISTRIBUTION FROM ADIPOSE TISSUE TO LIVER DURING REGENERATION IMPACTS HEPATOCYTE PROLIFERATION, AND SUGGEST A POTENTIAL STRATEGY TO BOOST LIVER REGENERATION. 2023 18 3112 35 GEOEPIDEMIOLOGY AND (EPI-)GENETICS IN PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A RARE FEMALE PREPONDERANT CHRONIC AUTOIMMUNE CHOLESTATIC LIVER DISEASE, CHARACTERIZED BY INTRAHEPATIC DUCTOPENIA AND PROGRESSIVE FIBROSIS. DURING LAST DECADES INCIDENCE AND PREVALENCE SHOWED AN INCREASING RATE WHICH VARY WIDELY WORLDWIDE DEMONSTRATING AN IMPORTANT INTERACTION BETWEEN ENVIRONMENTAL AND GENETIC FACTORS. HERITABILITY SUGGESTED BY FAMILIAL OCCURRENCE AND MONOZYGOTIC TWINS CONCORDANCE HAVE BEEN CONFIRMED IN MORE STUDIES. EPIGENETICS MECHANISMS SUCH AS HISTONE MODIFICATION AND DNA METHYLATION CAN PARTIALLY EXPLAIN PREDISPOSITION AND INHERITANCE OF THIS DISEASE. NEVERTHELESS, AN ASSOCIATION WITH SPECIFIC CLASS II HUMAN LEUKOCYTE ANTIGEN (HLA) VARIANTS HAVE BEEN REPORTED, SHOWING AN INCREASE RISK IN SUSCEPTIBILITY. MORE RECENTLY, DATA REGARDING A STRONG PROTECTIVE ASSOCIATION BETWEEN PBC AND HLA ALLELES CONFIRMED THIS ASSOCIATION. AFTER RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS), A MORE INTRICATE INTERACTION BETWEEN PBC AND THE HLA REGION HAS BEEN SHOWN. FURTHERMORE, GWAS ALSO IDENTIFIED SEVERAL IMMUNE-RELATED-GENES IMPLICATED. MORE GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE ARE NEEDED TO REACH A COMPLETE AND SYSTEMATIC KNOWLEDGE OF THIS DISEASE. IN THIS REVIEW WE DISCUSS MORE RECENT ISSUED DATA ON GEOEPIDEMIOLOGY OF PBC AND THE ROLE OF (EPI-)GENETIC MECHANISMS IN ITS PATHOGENESIS. 2018 19 5688 25 SILENCING EFFECTS OF MUTANT RAS SIGNALLING ON TRANSCRIPTOMES. MUTATED GENES OF THE RAS FAMILY ENCODING SMALL GTP-BINDING PROTEINS DRIVE NUMEROUS CANCERS, INCLUDING PANCREATIC, COLON AND LUNG TUMORS. BESIDES THE NUMEROUS EFFECTS OF MUTANT RAS GENE EXPRESSION ON ABERRANT PROLIFERATION, TRANSFORMED PHENOTYPES, METABOLISM, AND THERAPY RESISTANCE, THE MOST STRIKING CONSEQUENCES OF CHRONIC RAS ACTIVATION ARE CHANGES OF THE GENETIC PROGRAM. BY PERFORMING SYSTEMATIC GENE EXPRESSION STUDIES IN CELLULAR MODELS THAT ALLOW COMPARISONS OF PRE-NEOPLASTIC WITH RAS-TRANSFORMED CELLS, WE AND OTHERS HAVE ESTIMATED THAT 7 PERCENT OR MORE OF ALL TRANSCRIPTS ARE ALTERED IN CONJUNCTION WITH THE EXPRESSION OF THE ONCOGENE. IN THIS CONTEXT, THE NUMBER OF UP-REGULATED TRANSCRIPTS APPROXIMATES THAT OF DOWN-REGULATED TRANSCRIPTS. WHILE UP-REGULATED TRANSCRIPTION FACTORS SUCH AS MYC, FOSL1, AND HMGA2 HAVE BEEN IDENTIFIED AND CHARACTERIZED AS RAS-RESPONSIVE DRIVERS OF THE ALTERED TRANSCRIPTOME, THE SUPPRESSED FACTORS HAVE BEEN LESS WELL STUDIED AS POTENTIAL REGULATORS OF THE GENETIC PROGRAM AND TRANSFORMED PHENOTYPE IN THE BREADTH OF THEIR OCCURRENCE. WE THEREFORE HAVE COLLECTED INFORMATION ON DOWNREGULATED RAS-RESPONSIVE FACTORS AND DISCUSS THEIR POTENTIAL ROLE AS TUMOR SUPPRESSORS THAT ARE LIKELY TO ANTAGONIZE ACTIVE CANCER DRIVERS. TO BETTER UNDERSTAND THE ACTIVE MECHANISMS THAT ENTAIL ANTI-RAS FUNCTION AND THOSE THAT LEAD TO LOSS OF TUMOR SUPPRESSOR ACTIVITY, WE FOCUS ON THE TUMOR SUPPRESSOR HREV107 (ALIAS PLAAT3 [PHOSPHOLIPASE A AND ACYLTRANSFERASE 3], PLA2G16 [PHOSPHOLIPASE A2, GROUP XVI] AND HRASLS3 [HRAS-LIKE SUPPRESSOR 3]). INACTIVATING HREV107 MUTATIONS IN TUMORS ARE EXTREMELY RARE, HENCE EPIGENETIC CAUSES MODULATED BY THE RAS PATHWAY ARE LIKELY TO LEAD TO DOWN-REGULATION AND LOSS OF FUNCTION. 2023 20 5595 25 ROLES OF GENETIC PREDISPOSITION IN THE SEX BIAS OF PULMONARY PATHOPHYSIOLOGY, AS A FUNCTION OF ESTROGENS : SEX MATTERS IN THE PREVALENCE OF LUNG DISEASES. IN ADDITION TO STUDIES FOCUSED ON ESTROGEN MEDIATION OF SEX-DIFFERENT REGULATION OF SYSTEMIC CIRCULATIONS, THERE IS NOW INCREASING CLINICAL RELEVANCE AND RESEARCH INTERESTS IN THE PULMONARY CIRCULATION, IN TERMS OF SEX DIFFERENCES IN THE MORBIDITY AND MORTALITY OF LUNG DISEASES SUCH AS INHERENT-, ALLERGIC- AND INFLAMMATORY-BASED EVENTS. THUS, FEMALE PREDISPOSITION TO PULMONARY ARTERY HYPERTENSION (PAH) IS AN INEVITABLE TOPIC. TO BETTER UNDERSTAND THE NATURE OF SEXUAL DIFFERENTIATION IN THE PULMONARY CIRCULATION, AND HOW HERITABLE FACTORS, IN VIVO- AND/OR IN VITRO-ALTERED ESTROGEN CIRCUMSTANCES AND CHANGES IN THE LIVE ENVIRONMENT WORK IN CONCERT TO DISCERN THE SEX BIAS, THIS CHAPTER REVIEWS PULMONARY EVENTS CHARACTERIZED BY SEX-DIFFERENT FEATURES, CONCOMITANT WITH EXPLORATION OF HOW ALTERATIONS OF GENETIC EXPRESSION AND ESTROGEN METABOLISMS TRIGGER THE FEMALE-PREDOMINANT PATHOLOGICAL SIGNALING. WE ADDRESS THE FOLLOWING: PAH (SECT.7.2) IS CHARACTERIZED AS AN ESTROGENIC PROMOTION OF ITS INCIDENCE (SECT. 7.2.2), AS A FUNCTION OF SPECIFIC GERMLINE MUTATIONS, AND AS AN ESTROGEN-ELICITED PROTECTION OF ITS PROGNOSIS (SECT.7.2.1). MORE DETAIL IS PROVIDED TO INTRODUCE A LESS RECOGNIZED GENE OF EPHX2 THAT ENCODES SOLUBLE EPOXIDE HYDROLASE (SEH) TO DEGRADE EPOXYEICOSATRIENIC ACIDS (EETS). AS A SUSCEPTIBLE TARGET OF ESTROGEN, EPHX2/SEH EXPRESSION IS DOWNREGULATED BY AN ESTROGEN-DEPENDENT EPIGENETIC MECHANISM. INCREASES IN PULMONARY EETS THEN EVOKE A POTENTIATION OF PAH GENERATION, BUT MITIGATION OF ITS PROGRESSION, A PHENOMENON SIMILAR TO THE ESTROGEN-PARADOX REGULATION OF PAH. ADDITIONALLY, THE FEMALE SUSCEPTIBILITY TO CHRONIC OBSTRUCTIVE PULMONARY DISEASES (SECT. 7.3) AND ASTHMA (SECT.7.4), BUT LESS PREFERENCE TO COVID-19 (SECT. 7.5), AND ROLES OF ESTROGEN IN THEIR PATHOGENESES ARE BRIEFLY DISCUSSED. 2021